Epidermal growth factor and transforming growth factor‐alpha decrease gamma interferon receptors and induction of intercellular adhesion molecule (ICAM‐1) on cultured keratinocytes

Abstract

The link between the epidermal keratinocytes of the skin and the activated T lymphocytes of the immune system is mediated by a variety of cytokines, including gamma interferon (IFN-y). We studied the influence of keratinocyte mitogens such as transforming growth factor-alpha (TGF-a), epidermal growth factor (EGF), and somatomedin-C (SM-C) on the ligand binding of '2P-labelled IFN-y to cultured keratinocytes derived from normal appearing adult. human skin. Keratinocytes placed in a medium devoid of mitogens become growth arrested, and these quiescent cells expressed 2.4 times (28,900 versus 12,200 sitesicell) as many high affinity IFN-y receptors (Kd = 0.22 nM) compared to keratinocytes which were actively growing in medium containing TGF-a (25 ng/mI) or EGF (10 ngiml). The reduction in IFN-y receptor sites by TGF-aiEGF was mitogen specific, as adding SM-C (500 ng/ml) did not have any effect on ligand binding, although it similarily stimulated keratinocyte growth. The reduction in IFN-y receptors was time dependent, occurring primarily after 24-48 hours of change in tissue culture conditions. The reduction in the number of high affinity IFN-y receptors by TGFa/EGF had immunobiological consequences, because quiescent keratinocytes in basal medium had an increased expression of HLA-DR and intercellular adhesion molecule-1 (ICAM-1) induced by IFN-y, compared to actively growing TGF-a/ EGF treated keratinocytes. These results suggest that rapidly proliferating keratinocytes exposed to TGF-a/EGF but not SM-C are capable of altering their response to IFN-y by decreasing their number of cell surface high affinity receptors for IFN-?/

STAT1-Induced HLA Class I Upregulation Enhances Immunogenicity and Clinical Response to Anti-EGFR mAb Cetuximab Therapy in HNC Patients

“…Since EGFR signaling might downregulate IFNγ receptor1 (IFNRI) (25), providing a mechanism for synergistic effects of EGFR blockade with IFNγ for STAT1-mediated HLA upregulation, we evaluated levels of IFNRI after cetuximab treatment. Indeed, cetuximab increased the expression of IFNRI in several HNC cell lines tested, in an EGFR-dependent fashion (Fig.…”

Epidermal Growth Factor Receptor Inhibition Augments the Expression of MHC Class I and II Genes

“…These same ligands can attenuate the induction of MHCII genes by IFN-g (14). On the basis of this, we hypothesized that the transactivation of the EGFR following IFN-g exposure might establish a negative feedback loop and thereby limit MHCII molecule expression which is tightly regulated (15).…”

“…These same ligands can repress the induction of MHCII molecules by IFN-g (14). Therefore, we reasoned that inhibition of protease activity would block the release of EGFR ligands following IFN-g exposure and lead to a more robust induction of MHCII molecules.…”

“…5) whereby EGFR activation represses MHCI and MHCII molecule expression. This may occur via its effect on the IFN-g receptor complex (14), CIITA mRNA, and/or direct effects on the promoters of MHCI and MHCII genes. In addition to direct effects on CIITA mRNA levels, enzymes whose activity is modulated by EGFR signaling may directly alter CIITA protein levels and/or activity via posttranslation modifications (30).…”

EGFR inhibitors, MHC expression and immune responses : Can EGFR inhibitors be used as immune response modifiers?

“…10 Prior reports have demonstrated that if keratinocytes are treated simultaneously with an EGFR ligand and IFNγ, there is an attenuation of MHCII induction. 11 Based upon this, we hypothesized that EGFRIs would have the opposite effect and would therefore augment MHCII induction by IFNγ. Because MHCII gene expression is largely regulated at the level of transcription, we focused our initial studies on a critical transcriptional regulator of MHCII molecule expression, the MHCII transactivator named CIITA.…”